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Design of the First‐in‐Class, Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction
Author(s) -
Xu Shilin,
Aguilar Angelo,
Xu Tianfeng,
Zheng Ke,
Huang Liyue,
Stuckey Jeanne,
Chinnaswamy Krishnapriya,
Bernard Denzil,
FernándezSalas Ester,
Liu Liu,
Wang Mi,
McEachern Donna,
Przybranowski Sally,
Foster Caroline,
Wang Shaomeng
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201711828
Subject(s) - leukemia , chemistry , cancer research , gene , small molecule , microbiology and biotechnology , biology , biochemistry , genetics
The structure‐based design of M‐525 as the first‐in‐class, highly potent, irreversible small‐molecule inhibitor of the menin‐MLL interaction is presented. M‐525 targets cellular menin protein at sub‐nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL‐regulated gene expression in MLL leukemia cells. M‐525 demonstrates high cellular specificity over non‐MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co‐crystal structure of M‐525 in complex with menin firmly establish its mode of action. A single administration of M‐525 effectively suppresses MLL‐regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M‐525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.